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Assessing androgen sensitive RNA splicing patterns in LNCaP cells.

ABSTRACT: Our previous studies of proteomic-coupled-network analysis of AR protein interaction complexes (Paliouras et al., Integrative Biology, 2011) identified a number of proteins involved in RNA metabolism, specifically alternative RNA splicing. We selected two interacting RNA splicing proteins, SAM68 and DDX5 to examine RNA splicing events in prostate cancer (PCa). This analysis suggests a much more robust effect on RNA splicing with AR dictating either an exon-inclusion or -exclusion pathway. To establish the true physiological roles of AR in alternative RNA splicing, we opted to further examine the changes in global splicing profiles of LNCaP PCa cells, stimulated with and without androgens in conjunction with overexpression studies of SAM68 and DDX5.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176124 | GEO | 2021/06/04

REPOSITORIES: GEO

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SAM68-specific splicing is required for proper selection of alternative 3'UTR isoforms in the nervous system

Project description:Neuronal alternative splicing is dynamically regulated in a spatiotemporal fashion. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs governed by STARs remains unclear. We deciphered the alternative splicing programs of SAM68 and SLM1 proteins using transcriptomics. We reveal that SAM68 and SLM1 encode distinct alternative splicing programs; SAM68 preferentially controls alternative last exon (ALE) splicing. Interleukin 1-receptor accessory protein (Il1rap) is a novel target for SAM68. The usage of Il1rap ALEs results in mainly two variants encoding two functionally different isoforms, a membrane-bound (mIL1RAcP) and a soluble (sIL1RAcP) type. The brain exclusively expresses mIL1RAcP. SAM68 knockout results in remarkable conversion into sIL1RAcP in the brain, which significantly disturbs IL1RAcP neuronal function. Thus, we uncover the critical role of proper neuronal isoform selection through ALE choice by the SAM68-specific splicing program.

2019-12-29 | GSE110258 | GEO

Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity, and cellular functions

Project description:Sam68 is a member of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins and its role is modulated by post-translational modifications, including serine/threonine phosphorylation, that differ at various stages of the cell cycle. However, the molecular basis and mechanisms of these modulations remain largely unknown. Here, we combined mass spectrometry, NMR spectroscopy, and cell biology techniques to provide a comprehensive post-translational modification (PTM) mapping of Sam68 at different stages of the cell cycle in HEK293 and HCT116 cells. We established that Sam68 is specifically phosphorylated at T33 and T317 by Cdk1, and demonstrated that these phosphorylation events reduce the binding of Sam68 to RNA, control its cellular localization, and reduce its alternative splicing activity, leading to a reduction in the induction of apoptosis and an increase in the proliferation of HCT116 cells.

2023-03-11 | PXD032716 | Pride

SAM68 promotes Lung adenocarcinoma tumorigenesis by regulating cancer metabolic conversion through alternative splicing

Project description:The metabolic conversion of oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling the tumor metabolic switch is still not entirely clear. Here we demonstrate that SAM68 (gene name: KHDRBS1) as a splicing regulatory factor is frequently overexpressed in Lung adenocarcinoma (LUAD) and negatively correlated with the prognosis of LUAD patients. we find SAM68 promotes LUAD cells tumorigenesis and metastasis both in vitro and in vivo by regulating cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of Pyruvate kinase (PKM) pre-mRNAs, finally promoting the formation of PKM2. Mechanically, Sam68 interacted with the splicing repressor hnRNP A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated the PKM splicing regulation. Together, our work demonstrates key roles of SAM68 in the cancer metabolic conversion by regulating alternative splicing and SAM68 may be a promising therapeutic target for treating LUAD.This project looks into how SAM68 levels affect cancer cell phenotype in vitro

2020-11-04 | GSE149120 | GEO

Sam68 insures proper 3'-end pre-mRNA processing during germ cell differentiation

Project description:Male germ cells express the widest repertoire of transcript variants in mammalian tissues. Nevertheless, factors and mechanisms underlying such pronounced diversity are largely unknown. The splicing regulator Sam68 is highly expressed in meiotic cells and its ablation results in defective spermatogenesis. Herein, we uncover an extensive splicing program operated by Sam68 across meiosis, primarily characterized by alternative last exon (ALE) regulation in genes of functional relevance for spermatogenesis. Lack of Sam68 preferentially causes premature transcript termination at internal polyadenylation sites.

2019-03-12 | GSE122929 | GEO

Alternative splicing signatures in apoptosis related genes of human HeLa cells with RNAi targeting p68 RNA helicase-DDX5

Project description:Alternative splicing profiling of apopotosis related genes in human HeLa cells (cervical cancer cell line) transfected with a plasmid expressing shRNAs targetting p68 helicase (DDX5, DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) cloned into the pSuper expression vector compared to empty vector. Keywords: treated vs. untreated comparison; alternative splicing Two-condition experiment, where the p68 DDX5 gene product levels was inhibited by siRNA transfection and compared to transfection with the negative control (scrambled siRNA). Biological replicates: 2, all independently grown and harvested. A dye swapping technical duplicate was performed for each biological replicate. Samples were hybridized onto a 44290 feature array designed by ExonHit to detect splicing events in apopotosis related genes and manufactured by Agilent using in situ synthesis of oligonucleotides by SurePrint technology.

2011-01-21 | E-GEOD-20010 | biostudies-arrayexpress

Transcriptome analyses of AR-V7 and ARv567es

Project description:Although AR-V7 has been intensively studied, it remains unclear whether AR-V7 and other AR splicing variants can specifically activate a distinctive transcriptional program from the full-length AR (AR-FL), and whether AR-V7 may play a role in accelerating the metastatic progression of castration-resistant PCa (CRPC). In this study, we hypothesize that AR-V7 can drive a distinct transcription program from AR-FL in CRPC condition. To test this, we used LNCaP model with inducible overexpression of AR-V7 or AR-V7-S81A to examine the transcriptional function of AR-V7 and the role of S81 phosphorylation on AR-V7 transcriptome. We also studied the endogenous AR-V7 transcriptome in CWR-22Rv1 cells using siRNA against AR-V7. Lastly, we used LNCaP model with inducible overexpression of AR-V567es to examine the AR-V567es transcriptome.

2024-06-05 | GSE221141 | GEO

Coordinate regulation of alternative pre-mRNA splicing events by the human RNA chaperone proteins hnRNPA1 and DDX5

Project description:Alternative pre-messenger RNA (pre-mRNA) splicing is a post-transcriptional mechanism for controlling gene expression. Splicing patterns are determined by both RNA binding proteins and nuclear pre-mRNA structure. Here, we analyze pre-mRNA splicing patterns, RNA binding sites and RNA structures near these binding sites coordinately controlled by two splicing factors, the heterogeneous nuclear ribonucleoprotein hnRNPA1 and the RNA helicase DDX5. We identified thousands of alternative pre-mRNA splicing events controlled by these factors by RNA-seq following RNA interference. Enhanced CLIP (eCLIP) on nuclear extracts was used to identify protein-RNA binding sites for both proteins in the nuclear transcriptome. We found a significant overlap between hnRNPA1 and DDX5 splicing targets and that they share many closely linked binding sites as determined by eCLIP analysis. In vivo SHAPE chemical RNA structure probing data was used to model RNA structures near several exons controlled and bound by both proteins. Both sequence motifs and in vivo UV crosslinking sites for hnRNPA1 and DDX5 were used to map binding sites in their RNA targets and often these sites flanked regions of higher chemical reactivity suggesting an organized nature to nuclear pre-mRNPs. This work provides a first glimpse into the possible RNA structures surrounding pre-mRNA splicing factor binding sites.

2018-06-08 | GSE115442 | GEO

Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness

Project description:Both epigenetic and splicing regulation contribute to tumor progression, but the potential links between these two levels of gene-expression regulation in pathogenesis are not well understood. Here, we report that the mouse and human RNA helicases ddx17 and ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA- and chromatin-binding factors, including the macroH2A1 histone. We show that macroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. In particular, the SOD3 gene that encodes the extracellular superoxide dismutase and plays a part in cell migration is regulated in an inverse manner by macroH2A1 splicing isoforms. These findings reveal a new regulatory pathway in which splicing factors control the expression of histone-variant isoforms that in turn drive a transcription program to switch tumor cells to an invasive phenotype. We analyzed 4T1 cells depleted or not for ddx5 and ddx17 RNA helicases using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. Four techinical replicates were performed. We analyzed 4T1 cells depleted for ddx5 and ddx17 RNA helicases and macroH2A1.1 or macroH2A1.2 using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. Three techinical replicates were performed.

2012-09-11 | E-GEOD-40737 | biostudies-arrayexpress

Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development

Project description:The paralog RNA binding proteins (RBPs) Sam68 and SLM2 are co-expressed in the cerebral cortex and display very similar splicing activity. However, their relative function(s) in this context is unknown. By performing a time-course analysis, we found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that are sensitive to concomitant ablation of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in the Sam68:Slm2dko developing cortex. Sam68:Slm2dko mice die perinatally with defects in neurogenesis and in neuronal differentiation, and the development of a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that maintenance of the Sam68 and Slm2 paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program while ensuring a robust redundant mechanism that supports proper cortical development.

2024-02-12 | GSE229749 | GEO

SAM68 is a splicing regulator in triple negative breast cancer

Project description:SAM68 is an RNA binding protein frequently up-regulated in several human cancers and its oncogenic activity has often been associated with its splicing activity. Nevertheless, the genome-wide impact of SAM68 on the transcriptome of cancer cells is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 SAM68-silenced cells, we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this splicing factor.

2022-04-04 | GSE140754 | GEO

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